NIAID Now | July 23, 2019
NIAID scientists have improved a technique to convert adult hematopoietic stem cells (HSCs) into a fetal-like form. This advance may bring researchers closer to the goal of transplanting fetal-like HSCs into fetuses that are diagnosed in the womb with a life-threatening blood or immune system disorder.
HSCs are immature cells that can develop into all types of blood cells. HSC transplants can cure an array of blood and immune system disorders, including some primary immune deficiency diseases, anemia, sickle cell disease and blood cancers. Today, such transplants usually are performed by transferring adult HSCs from the bone marrow of a healthy donor to a child or adult. However, infants who are born with certain blood and immune system disorders may face imminent death or disability without an HSC transplant soon after birth. Some experts believe that in cases where these diseases are diagnosed before birth, it would be advantageous to perform an HSC transplant to the fetus. It may be most effective to perform such a transplant with fetal HSCs, but these are difficult if not impossible to obtain. An alternative and plentiful source of fetal-like HSCs could potentially become available if scientists knew how to revert adult HSCs into fetal form in the laboratory.
Researchers led by Stefan Muljo, Ph.D., at the NIAID Laboratory of Immune System Biology demonstrated in 2012 that it is possible in principle to engineer fetal-like HSCs from adult ones using an RNA-binding protein called Lin28b. In general, RNA-binding proteins play a direct role in orchestrating which genes in a cell are converted into proteins. Subsequent studies by Dr. Muljo and colleagues revealed that Lin28b did not completely revert adult HSCs into fetal-like ones, however. The team searched for molecules that would cooperate with Lin28b and, after years of investigations, found one: another RNA-binding protein called Igf2bp3. The scientists then demonstrated that they could generate fetal-like HSCs better using Lin28b and Igf2bp3 together than using either protein alone.
To test the effect of the two proteins on HSCs in a live organism, the investigators extracted HSCs from the bone marrow of adult mice and engineered the cells to make Lin28b and Igf2bp3. Then they transplanted these engineered HSCs into immunodeficient mice. The mice that received the transplants underwent B-cell development resembling the embryonic and fetal waves of development that normally occur early in life. This demonstrated that the two proteins had indeed reverted the adult HSCs to a fetal-like form.
Although the scientists uncovered thousands of genes that are regulated by these two proteins, it remains unclear exactly how the proteins convert adult HSCs into fetal-like ones. This question will be the subject of future research.
J Yuan et al. Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science DOI: 10.1126/science.1216557 (2012)
S Wang, B Chim et al. Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3. Genes and Development DOI: 10.1101/gad.325100.119 (2019)